US20040185108A1 - Method of preparing gas-filled polymer matrix microparticles useful for delivering drug - Google Patents

Method of preparing gas-filled polymer matrix microparticles useful for delivering drug Download PDF

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US20040185108A1
US20040185108A1 US10/390,974 US39097403A US2004185108A1 US 20040185108 A1 US20040185108 A1 US 20040185108A1 US 39097403 A US39097403 A US 39097403A US 2004185108 A1 US2004185108 A1 US 2004185108A1
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drug
microparticles
polymer
composition according
gas
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Robert Short
Thomas Ottoboni
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Point Biomedical Corp
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Assigned to POINT BIOMEDICAL CORPORATION reassignment POINT BIOMEDICAL CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: OTTOBONI, THOMAS B., SHORT, ROBERT E.
Priority to EP04719318A priority patent/EP1608340A4/de
Priority to PCT/US2004/007529 priority patent/WO2004082607A2/en
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5089—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin

Definitions

  • This invention pertains to drug delivering compositions and a method of preparing gas-filled microparticles having a polymer matrix interior which are useful for ultrasound mediated targeted delivery of a drug.
  • Ultrasound is a modern medical imaging modality using sound energy to noninvasively visualize the interior structures and organs of a patient.
  • Pulses of high frequency sound generally in the megaHertz (MHz) range, emitted from a hand-held transducer are propagated into the body where they encounter different surfaces and interfaces. A portion of the incident sound energy is reflected back to the transducer that converts the sound waves into electronic signals which are then presented as a two-dimensional echographic image on a display monitor.
  • MHz megaHertz
  • ultrasound contrast agents Use of contrast agents enables the sonographer to visualize the vascular system which is otherwise relatively difficult to image.
  • ultrasound contrast injected into the bloodstream permits the cardiologist to better visualize heart wall motion with the opacification of the heart chambers.
  • contrast can be used to assess perfusion of blood into the myocardium to determine the location and extent of damage caused by an infarct.
  • visualization of blood flow using ultrasound contrast in other organs such as the liver and kidneys has found utility in diagnosing disease states in these organs.
  • microbubbles can be designed to rupture when exposed to ultrasound. Accordingly, a gas-filled microparticle that is rupturable when exposed to ultrasound also has potential in applications where site-specific delivery of a drug is desired.
  • gas-filled ultrasound contrast agents serving also as drug carriers has been described for gas-filled liposomes in U.S. Pat. No. 5,580,575.
  • a quantity of liposomes containing drug is administered into the circulatory system of a patient and monitored using ultrasonic energy at diagnostic levels until the presence of the liposomes is detected in the region of interest.
  • Ultrasonic energy is then applied to the region at a power level that is sufficient to rupture the liposomes thus releasing the drug.
  • the ultrasonic energy is described in U.S. Pat. No. 5,558,082 to be applied by a transducer that simultaneously applies diagnostic and therapeutic ultrasonic waves from transducer elements located centrally to the diagnostic transducer elements.
  • This invention pertains to a novel drug containing gas-filled polymer matrix microparticles suitable for use as an ultrasound contrast agent and for the ultrasound mediated delivery of a drug and methods of preparation of same.
  • a method of preparation comprises the steps of:
  • Step 2 may be modified such that the aqueous medium also contains a biologically compatible amphiphilic material which encapsulates the emulsion droplets. Upon crosslinking, the amphiphilic material becomes a contiguous outer layer of the microparticle.
  • the method may also include, after step 2, the step of replacing the aqueous medium with a second aqueous medium.
  • This additional step is useful when the components of an aqueous medium optimized for emulsion of the polymer solution are different from the components of an aqueous medium optimized for lyophilization.
  • the additional step may be achieved by centrifugation or by diafiltration.
  • Also provided is a method of delivering a drug to an organ or tissue of a patient comprising the steps of:
  • FIG. 1 is a plot of frame number vs. acoustic densitometry backscatter taken on an ultrasonic scanner as described in Example 7 for a test of the microparticles made in accordance with Example 1.
  • FIG. 2 is a plot of sound intensity in MI 2 vs. peak backscatter as described in Example 7.
  • FIG. 3 is a plot of sound intensity in MI 2 vs. fragility slope as described in Example 7.
  • the present invention provides drug-containing gas-filled porous microparticles having a polymer matrix interior.
  • Such microparticles are useful as an ultrasonic contrast agent and for site-specific delivery of a drug.
  • These microparticles being porous, rely on the hydrophobicity of the polymer to retain the gas within.
  • the microparticles may be produced to also include an outer layer of a biologically compatible amphiphilic material, thus providing a surface for chemical modification to serve various purposes.
  • Microparticles can be fabricated to encapsulate both a drug and a gas. These microparticles can then be dispersed within the bloodstream and insonated with ultrasound at an intensity sufficient to cause the microparticles to rupture thereby releasing the drug into the surrounding medium. Thus, the circulating microparticles do not release their drug payload until they are triggered to do so using ultrasound.
  • a drug may be selectively delivered to heart tissue by first injecting intravenously a suspension of drug-containing microbubbles and then focusing an ultrasound beam on the heart to rupture the microbubbles that are perfusing the heart tissues. This type of drug delivery system is particularly advantageous when toxicity from systemic delivery of the drug is a concern. By limiting release of a pharmaceutical agent to a specific targeted site, toxic side effects can be minimized. In addition, total required dosage will typically be lower and result in a decrease in costs for the patient.
  • a class of therapeutic moieties deliverable by microbubbles triggered by ultrasound is chemotherapeutic agents used for the treatment of various cancers. Most of these agents are delivered by intravenous administration and can produce significant systemic side effects and toxicities that limit their dose and overall use in the treatment of cancer.
  • doxorubicin is a chemotherapy drug indicated for the treatment of breast carcinoma, ovarian carcinoma, thyroid carcinoma, etc.
  • the use of doxorubicin is limited by its irreversible cardiotoxicity, which may be manifested either during, or months to years after termination of therapy.
  • Other side effects commonly associated with chemotherapeutic agents include hematologic toxicity and gastrointestinal toxicity.
  • carmustine is associated with pulmonary, hematologic, gastrointestinal, hepatic, and renal toxicities.
  • the utility of doxorubicin, carmustine, and other chemotherapy agents with a narrow therapeutic index may be improved by delivering the drug at the tumor site in high concentrations using ultrasound-triggered microparticles while reducing the systemic exposure to the drug.
  • the process for the manufacture of the porous microparticles of the present invention utilizes a different emulsion solvent removal technique from those typically used to produce solid polymer microspheres.
  • the solvent undergoing phase change is evaporated.
  • solvent removal is effected by sublimation through a lyophilization process.
  • a lyophilization process mobile polymer molecules in the liquid phase will cohere to form a solid microsphere when solvent is removed.
  • the initial freezing step in lyophilization immobilizes the polymer molecules so that when solvent is removed under vacuum, a network of interstitial void spaces surrounded by a web-like polymer structure remains. This porous structure can then be filled with a gas.
  • the fabrication of the matrix microparticles starts with the preparation of the water-immiscible solvent solution with polymer and drug dissolved therein.
  • Preferred polymers are biodegradable synthetic polymers such as polylactide, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, polyglycolide and copolymers or mixtures of two or more thereof.
  • the requirements for the polymer solvent are that it is substantially water-immiscible and practicably lyophilizable.
  • practicably lyophilizable it is meant that the solvent freezes at a temperature well above the temperature of a typical lyophilizer minimum condensing capability and that the solvent will sublimate at reasonable rate in vacuo.
  • Suitable solvents include p-xylene, cyclooctane, benzene, decane, undecane, cyclohexane and the like.
  • a preferred polymer is polylactide and the preferred solvent is p-xylene.
  • the drug is lipophilic and thus relatively soluble in the organic polymer solutions while relatively insoluble in the aqueous phase.
  • the counterion of the drug can greatly impact its lipophilicity.
  • the neutral form of an ionizable molecule is typically more lipophilic than its ionic form.
  • a drug that is ionizable in aqueous solution would be incorporated into the microsphere in its neutral, or free base form, or in its ionic form with a counterion that increases the overall lipophilicity of the molecule.
  • the word drug refers to chemicals, or biological molecules providing a therapeutic, diagnostic, or prophylactic effect in vivo.
  • Drugs contemplated for use in the present invention include but are not limited to the following classes: antibiotics, antifungal, anti-inflammatory, antineoplastic, immunosuppressive, antianginal, antiarrhythmic, antiarthritic, antibacterial, anticoagulants, thrombolytic, antifibrinolytic, antiplatelet, antiviral, antimicrobial, anti-infective, steroidal compound, hormones, proteins, and nucleic acids.
  • the concentration of polymer in solution will dictate the void volume of the end product that will, in turn, impact acoustic performance.
  • a high concentration provides lower void volume and a more acoustically durable microparticle.
  • a lower concentration will result in a more fragile microparticle.
  • Polymer molecular weight also has an effect.
  • a low molecular weight polymer produces a more fragile particle.
  • additives may be used in the polymer organic phase.
  • Plasticizers to modify elasticity of the polymer or other agents to affect hydrophobicity of the microparticle can be added to modify the mechanical, and thus acoustic, characteristics of the microparticle.
  • plasticizers include the phthalates or ethyl citrates.
  • Agents to modify hydrophobicity include fatty acids and waxes.
  • the polymer/drug solution is then emulsified in an aqueous phase.
  • the aqueous phase may contain a surface-active component to enhance microdroplet formation and provide emulsion stability for the duration of the fabrication process.
  • Surface-active components include the poloxamers, tweens, and brijs. Also suitable are amphiphilic water-soluble proteins such as gelatin, casein, albumin, or synthetic polymers such as polyvinyl alcohol.
  • viscosity enhancers may also be beneficial as an aid in stabilizing the emulsion.
  • Useful viscosity enhancers include carboxymethyl cellulose, dextran, methyl cellulose, hydroxyethyl cellulose, polyvinyl pyrrolidone, and various natural gums such as gum arabic, carrageenan, and guar gum.
  • the range of ratios of the organic phase to the aqueous phase is typically between 2:1 and 1:20 with a 2:1 to 1:3 ratio range preferred.
  • aqueous phase is also to serve as the suspending medium during the lyophilization step
  • other components which may be included in the aqueous phase are ingredients suitable as bulking agents such as polyethylene glycol, polyvinyl pyrrolidone, sugars such as glucose, sucrose, lactose, and mannitol. Salts such as sodium phosphate, sodium chloride or potassium chloride may also be included to accommodate tonicity and pH requirements.
  • a variety of equipment may be used to perform the emulsification step including colloid mills, rotor-stator homogenizers, ultrasonic homogenizers, high pressure homogenizers, microporous membrane homogenizers, with microporous membrane homogenization preferred because the more uniform shearing provides for a more monodisperse population of emulsion droplets.
  • Size of the droplets formed should be in a range that is consistent with the application. For example, if the microparticles are to be injected intravenously into a subject, then they should have diameters of less than 10 microns in order to pass unimpeded through the capillary network.
  • the size control can be empirically determined by calibration on the emulsification equipment.
  • the material is first solubilized in the aqueous phase.
  • This outer layer material will typically be amphiphilic, that is, have both hydrophobic and hydrophilic characteristics. Such materials have surfactant properties and thus tend to be deposited and adhere to interfaces such as the outer surface of the emulsion droplets.
  • Preferred materials are proteins such as collagen, gelatin, casein, serum albumin, or globulins. Human serum albumin is particularly preferred for its blood compatibility. Synthetic polymers may also be used such as polyvinyl alcohol.
  • the deposited layer of amphiphilic material can be further stabilized by chemical crosslinking.
  • suitable chemical crosslinkers include the aldehydes like formaldehyde and glutaraldehyde or the carbodiimides such as dimethylaminopropyl ethylcarbodiimide hydrochloride.
  • sodium tetraborate may be used to crosslink polyvinyl alcohol.
  • Provision for the outer layer is preferably achieved by diluting the prepared emulsion into an aqueous bath containing the dissolved chemical crosslinker.
  • This outer crosslinked layer also has the advantage of increasing the stability of the emulsion droplets during the later processing steps.
  • Provision of a separate outer layer also allows for charge and chemical modification of the surface of the microparticles without being limited by the chemical or physical properties of material present inside the microparticles.
  • Surface charge can be selected, for example, by providing an outer layer of a type “A” gelatin having an isoelectric point above physiological pH or by using a type “B” gelatin having an isoelectric point below physiological pH.
  • the outer surface may also be chemically modified to enhance biocompatibility, such as by pegylation, succinylation, or amidation, as well as being chemically binding to the surface targeting moiety for binding to selected tissues.
  • the targeting moieties may be antibodies, cell receptors, lectins, selectins, integrins, or chemical structures or analogues of the receptor targets of such materials.
  • the outer aqueous phase may be replaced by a second aqueous phase.
  • Replacement may be achieved by means of diafiltration or by centrifugation.
  • the emulsion is then lyophilized. This involves first freezing both the water immiscible organic phase in the emulsion droplets and the suspending aqueous phase, then removing both phases by sublimation in vacuo. The process produces a dry cake containing porous polymer matrix microparticles with drug incorporated therein.
  • the drug-containing microparticles are porous and thus can receive a gas. Introducing a selected gas into the lyophilization chamber after the drying step will fill the interstitial voids within the microparticle matrix interior. Alternatively, the gas introduced into the microparticle upon pressurization of the lyophilization chamber can be exchanged for a second gas.
  • Any gas may be used, but biologically inert gases such as air, nitrogen, helium, oxygen, xenon, argon, helium, carbon dioxide, and halogenated hydrocarbons such as perfluorobutane, perfluoropropane or sulfur halides such as sulfur hexafluoride are preferred.
  • biologically inert gases such as air, nitrogen, helium, oxygen, xenon, argon, helium, carbon dioxide, and halogenated hydrocarbons such as perfluorobutane, perfluoropropane or sulfur halides such as sulfur hexafluoride are preferred.
  • perfluorocarbons have low solubility while carbon dioxide has very high solubility. Such differences in solubility will influence the acoustic performance of the microparticle.
  • the polymer solvent and the water of the excipient suspending medium are removed at reduced pressure by sublimation to form a population of substantially solvent free microparticles having a polymer matrix interior.
  • the incorporated drug will remain within the polymer matrix until the microparticle is made to rupture in the bloodstream using ultrasound.
  • the dry lyophilized product is reconstituted by addition of an aqueous solution and the resulting microparticle suspension intravenously injected.
  • the drug-containing gas-filled microparticles circulate systemically, their presence at the site of delivery can be monitored using an ultrasound device operating at power levels below what is required to rupture the microparticles. Then at the appropriate time, when a required concentration of microparticles is present at the site, the power level can be increased to a level sufficient to rupture and flood the microparticles, thus triggering the release of the drug payload.
  • the rupture of the drug-containing microparticles is achieved using ultrasound scanning devices and employing transducers commonly utilized in diagnostic contrast imaging.
  • a single ultrasound transducer may be employed for both imaging and rupturing of the microparticles by focusing the beam upon the target site and alternately operating at low and high power levels as required by the application.
  • a plurality of transducers focused at the region may be used so that the additive wave superposition at the point of convergence creates a local intensity sufficient to flood the microparticles.
  • a separate imaging transducer may be used to image the region for treatment.
  • microparticles be rupturable for drug release at power levels below the clinically accepted levels for diagnostic imaging. Specific matching of ultrasound conditions and microparticle response to such conditions achieve controlled release conditions.
  • Preferred acoustic conditions for rupture are those at a power, frequency, and waveform sufficient to provide a mechanical index from about 0.1 to about 1.9.
  • aqueous solution of 1% polyvinyl alcohol and 2.8% mannitol was prepared.
  • a polymer solution containing 6% poly DL-lactide in p-xylene was prepared.
  • To 40.0 g of the polymer solution was combined 50.0 g of the aqueous solution in a jacketed beaker maintained at 30° C.
  • the mixture was then emulsified to create an oil-in-water emulsion using a circulating system consisting of a peristaltic pump and a sintered metal filter having a nominal pore size of 7 microns.
  • a solution of 5.4% human serum albumin (hsa) was prepared by dilution of a 25% solution and the pH adjusted to 4 with HCl. Separately, 0.99 gm poly D-L lactide was dissolved in 29.0 gm p-xylene. In a jacketed beaker maintained at 40° C., the polylactide solution was combined with 30 gms of the previously prepared hsa solution and a coarse emulsion was formed using magnetic stirring. A peristaltic pump was used to pump the coarse emulsion through a porous sintered metal filter element with a 2 ⁇ m nominal pore size.
  • the emulsion was recirculated through the element for approximately 15 minutes until the average droplet size was less than 10 microns.
  • the emulsion was diluted into 350 ml of a 40° C. aqueous bath containing 1.0 ml of a 25% glutaraldehyde solution and 1.4 ml of 1N NaOH. After 15 minutes, 0.75 gm of poloxamer 188 surfactant was dissolved into the aqueous bath.
  • the emulsion microdroplets were retrieved by centrifugation at 2000 rpm for 10 minutes, formulated into an aqueous solution containing polyethylene glycol, glycine, and poloxamer 188, dispensed into 10 ml vials, and then lyophilized. After the drying cycle was completed, nitrogen gas was introduced into the lyophilization chamber to a pressure slightly less than atmospheric and the vials were stoppered.
  • a solution of 1% Fluorescent Yellow Dye R (Keystone PIN 806-043-50) and 6% poly DL-lactide was prepared in xylene. Separately, an aqueous solution containing 1% polyvinyl alcohol and 2.8% mannitol was prepared. In a jacketed beaker maintained at 30° C., 40 gm of the dye containing polylactide solution was combined with 50 gms of the prepared aqueous solution and a coarse emulsion was formed using magnetic stirring. A peristaltic pump was used to pump the coarse emulsion through a porous sintered metal filter element with a 7 ⁇ m nominal pore size.
  • the emulsion was recirculated through the element for approximately 6 minutes until the average droplet size was less than 10 microns.
  • the emulsion was diluted with stirring into 400 ml of a 30° C. aqueous bath containing 2.8% mannitol. After 15 minutes, the emulsion was dispensed into 10 mL vials and lyophilized. After the drying cycle was completed, nitrogen gas was introduced into the lyophilization chamber to a pressure slightly less than atmospheric and the vials were stoppered.
  • control sample remained undisturbed for 2 hours to allow the dye-containing microparticles to float.
  • the subnatant was removed and centrifuged at 14,000 rpm for 2 minutes.
  • the experimental sample was sonicated for 1 minute on level 5 using a Virtis Virsonic hand-held sonicator. Microscopic inspection of the suspension revealed that the microparticles had become flooded as a result of the sonication procedure.
  • the suspension was centrifuged at 14,000 rpm for 2 minutes.
  • the supernatants from both the control and the experimental samples were read on a spectrophotometer using a wavelength of 463 nm.
  • a standard curve of Fluorescent Yellow Dye R concentration verses absorbance at 463 nm was generated and was found to be linear. The amount of dye in each sample was calculated, from the absorbance using the standard curve. The concentration of Fluorescent Yellow Dye R in the control was 1.76 ⁇ g/mL while the experimental sample contained 5.06 ⁇ g/mL thus demonstrating the release of dye from the prepared polymer matrix microparticles using ultrasound.
  • a solution of 1% oxybutynin and 6% poly DL-lactide was prepared in xylene. Separately, an aqueous solution containing 1% polyvinyl alcohol and 2.8% mannitol was prepared and the pH was adjusted to 8 using NaOH. In a jacketed beaker maintained at 30° C., 40 gm of the oxybutynin containing polylactide solution was combined with 50 gms of the prepared aqueous solution and a coarse emulsion was formed using magnetic stirring. A peristaltic pump was used to pump the coarse emulsion through a porous sintered metal filter element with a 7 ⁇ m nominal pore size.
  • the emulsion was recirculated through the element for approximately 6 minutes until the average droplet size was less than 10 microns.
  • the emulsion was diluted with stirring into 400 ml of a 30° C. aqueous bath containing 2.8% mannitol and at a pH of 8. After 15 minutes of stirring, the emulsion was dispensed into 10 mL vials and lyophilized. After the drying cycle was completed, nitrogen gas was introduced into the lyophilization chamber to a pressure slightly less than atmospheric and the vials were stoppered.
  • control sample contained 0.03 mg oxybutynin/vial, while the experimental sample contained 1.05 mg/vial.
  • the control sample had 0.65 mg oxybutynin/vial and the experimental sample had 1.93 mg/vial.
  • Theoretical loading was 2.4 mg/vial.
  • An Agilent 5500 ultrasonic scanner was used for this study to measure the acoustic backscatter and fragility from a suspended matrix particle.
  • This scanner has the capability of measuring the acoustic density (AD) as a function of time within a region of interest (ROI) displayed on the video monitor.
  • the scanner was set to the 2D harmonic mode with send frequency of 1.8 MHz and receive frequency of 3.6 MHz.
  • the test cell was a 2 cm diameter tube running the length of a Doppler flow phantom manufactured by ATL Laboratories of Bridgeport, Conn.
  • Microparticle agent made in accordance with Example 1 was first reconstituted with deionized water.
  • the resulting suspension was diluted into a 1 liter beaker containing water and then circulated through the flow phantom using a peristaltic pump (Masterflex L/S manufactured by Cole-Parmer). To insure that the agent remained uniformly suspended in the beaker, mixing using a VWR Dylastir magnetic stirrer in conjunction with a 2 cm coated plastic stir bar was maintained throughout the duration of the testing. When data was to be collected, the pump was turned off resulting in no flow within the phantom.
  • the scanner transducer (s4 probe) was placed directly over the flow phantom within a water-well designed into the phantom. It was oriented 90 degrees to the flow axis such that the image of the flow tube on the monitor was circular.
  • the ROI (21 ⁇ 21) was positioned by the operator within the image of the tubing lumen to be at the top center about 1 mm away from the top wall and free of any bright echoes caused by the wall.
  • the scanner was set to the acoustic densitometry (AD) mode. This mode permits the scanner to read the mean densitometry within the ROI as a function of time using a triggered mode.
  • the triggering interval was selected to be 200 milliseconds.
  • the agent at fragility slope ⁇ 17.4 the agent begins to fail at an MI 2 value of intensity of 0.0868, which is a value of MI of 0.295.
  • MI 2 value of intensity of 0.0868 which is a value of MI of 0.295.

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EP04719318A EP1608340A4 (de) 2003-03-18 2004-03-10 Verfahren zur herstellung gasgefüllter polymermatrix-mikropartikel zur verwendung bei der wirkstofffreisetzung
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060141050A1 (en) * 2002-03-26 2006-06-29 Lerner Itzhak E Drug microparticles
US20080213355A1 (en) * 2005-07-22 2008-09-04 Koninklijke Philips Electronics, N.V. Method and System for in Vivo Drug Delivery
WO2009075583A1 (en) * 2007-12-10 2009-06-18 Epitarget As Use of particles comprising an alcohol
US20120183949A1 (en) * 2011-01-19 2012-07-19 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Method, device, or system using lung sensor for detecting a physiological condition in a vertebrate subject
US8466206B1 (en) * 2011-12-22 2013-06-18 Eastman Kodak Company Process for preparing porous polymer particles

Citations (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3743604A (en) * 1969-01-09 1973-07-03 Bayer Ag Process for the production of microcapsules
US4718433A (en) * 1983-01-27 1988-01-12 Feinstein Steven B Contrast agents for ultrasonic imaging
US5041292A (en) * 1988-08-31 1991-08-20 Theratech, Inc. Biodegradable hydrogel matrices for the controlled release of pharmacologically active agents
US5102983A (en) * 1990-04-02 1992-04-07 United States Surgical Corporation Process for preparing foamed, bioabsorbable polymer particles
US5190766A (en) * 1990-04-16 1993-03-02 Ken Ishihara Method of controlling drug release by resonant sound wave
US5271961A (en) * 1989-11-06 1993-12-21 Alkermes Controlled Therapeutics, Inc. Method for producing protein microspheres
US5310540A (en) * 1990-10-05 1994-05-10 Sintetica Sa Method for the preparation of stable suspensions of hollow gas-filled microspheres suitable for ultrasonic echography
US5425366A (en) * 1988-02-05 1995-06-20 Schering Aktiengesellschaft Ultrasonic contrast agents for color Doppler imaging
US5456917A (en) * 1993-04-12 1995-10-10 Cambridge Scientific, Inc. Method for making a bioerodible material for the sustained release of a medicament and the material made from the method
US5501863A (en) * 1990-02-09 1996-03-26 Schering Aktiengesellschaft Contrast media synthesized from polyaldehydes
US5518709A (en) * 1991-04-10 1996-05-21 Andaris Limited Preparation of diagnostic agents
US5558082A (en) * 1995-01-09 1996-09-24 Spencer; Robert F. Method of intubating a patient and introducer for use with such method
US5562893A (en) * 1994-08-02 1996-10-08 Molecular Biosystems, Inc. Gas-filled microspheres with fluorine-containing shells
US5565215A (en) * 1993-07-23 1996-10-15 Massachusettes Institute Of Technology Biodegradable injectable particles for imaging
US5569468A (en) * 1994-02-17 1996-10-29 Modi; Pankaj Vaccine delivery system for immunization, using biodegradable polymer microspheres
US5580575A (en) * 1989-12-22 1996-12-03 Imarx Pharmaceutical Corp. Therapeutic drug delivery systems
US5611344A (en) * 1996-03-05 1997-03-18 Acusphere, Inc. Microencapsulated fluorinated gases for use as imaging agents
US5620883A (en) * 1994-04-01 1997-04-15 The Johns Hopkins University Living cells microencapsulated in a polymeric membrane having two layers
US5679377A (en) * 1989-11-06 1997-10-21 Alkermes Controlled Therapeutics, Inc. Protein microspheres and methods of using them
US5711933A (en) * 1990-05-18 1998-01-27 Bracco International B.V. Method of making polymeric gas or air filled microballoons for ultrasonic echography
US5741522A (en) * 1991-07-05 1998-04-21 University Of Rochester Ultrasmall, non-aggregated porous particles of uniform size for entrapping gas bubbles within and methods
US5837221A (en) * 1996-07-29 1998-11-17 Acusphere, Inc. Polymer-lipid microencapsulated gases for use as imaging agents
US5870275A (en) * 1993-12-03 1999-02-09 Sanyo Chemical Industries, Ltd. Electrolyte and electronic component using same
US5886520A (en) * 1995-01-24 1999-03-23 Canon Kabushiki Kaisha Position sensor having magnetic resistance effect devices for detecting a position of an object
US5919434A (en) * 1993-09-03 1999-07-06 Nycomed Imaging As Polymeric surfactant-encapsulated microbubbles and their use in ultrasound imaging
US5922304A (en) * 1989-12-22 1999-07-13 Imarx Pharmaceutical Corp. Gaseous precursor filled microspheres as magnetic resonance imaging contrast agents
US5948387A (en) * 1990-06-01 1999-09-07 Imarx Pharmaceutical Corp. Contrast media for ultrasonic imaging
US6045777A (en) * 1997-06-30 2000-04-04 Acusphere, Inc. Method for enhancing the echogenicity and decreasing the attenuation of microencapsulated gases
US6071496A (en) * 1988-02-05 2000-06-06 Scharing Aktiengesellschaft Polyalkylcyanoacrylate agents and methods for enhancing contrast in ultrasound imaging
US6143276A (en) * 1997-03-21 2000-11-07 Imarx Pharmaceutical Corp. Methods for delivering bioactive agents to regions of elevated temperatures
US6193951B1 (en) * 1997-04-30 2001-02-27 Point Biomedical Corporation Microparticles useful as ultrasonic contrast agents
US6254852B1 (en) * 1999-07-16 2001-07-03 Dupont Pharmaceuticals Company Porous inorganic targeted ultrasound contrast agents
US6333021B1 (en) * 1994-11-22 2001-12-25 Bracco Research S.A. Microcapsules, method of making and their use
US6443898B1 (en) * 1989-12-22 2002-09-03 Imarx Pharmaceutical Corp. Therapeutic delivery systems
US20030215394A1 (en) * 2002-05-17 2003-11-20 Short Robert E. Microparticles having a matrix interior useful for ultrasound triggered delivery of drugs into the bloodstream
US20050043816A1 (en) * 2003-05-15 2005-02-24 Arindam Datta Reticulated elastomeric matrices, their manufacture and use in implantable devices
US20050043585A1 (en) * 2003-01-03 2005-02-24 Arindam Datta Reticulated elastomeric matrices, their manufacture and use in implantable devices
US6919068B2 (en) * 2002-05-17 2005-07-19 Point Biomedical Corporation Method of preparing gas-filled polymer matrix microparticles useful for echographic imaging

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR0181252B1 (ko) * 1996-12-31 1999-03-20 박원훈 에멀젼 방법에 의한 다공성 매트릭스형 서방성 제제의 제조방법
WO2001012071A1 (en) * 1999-08-13 2001-02-22 Point Biomedical Corporation Microparticles useful as ultrasonic contrast agents and for lymphatic system

Patent Citations (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3743604A (en) * 1969-01-09 1973-07-03 Bayer Ag Process for the production of microcapsules
US4718433A (en) * 1983-01-27 1988-01-12 Feinstein Steven B Contrast agents for ultrasonic imaging
US6071496A (en) * 1988-02-05 2000-06-06 Scharing Aktiengesellschaft Polyalkylcyanoacrylate agents and methods for enhancing contrast in ultrasound imaging
US6177062B1 (en) * 1988-02-05 2001-01-23 Schering Aktiengesellschaft Agents and methods for enhancing contrast in ultrasound imaging
US6264959B1 (en) * 1988-02-05 2001-07-24 Schering Aktiengesellschaft Ultrasonic contrast agents, process for their preparation and their use as a diagnostic and therapeutic agent
US5425366A (en) * 1988-02-05 1995-06-20 Schering Aktiengesellschaft Ultrasonic contrast agents for color Doppler imaging
US5041292A (en) * 1988-08-31 1991-08-20 Theratech, Inc. Biodegradable hydrogel matrices for the controlled release of pharmacologically active agents
US5271961A (en) * 1989-11-06 1993-12-21 Alkermes Controlled Therapeutics, Inc. Method for producing protein microspheres
US5679377A (en) * 1989-11-06 1997-10-21 Alkermes Controlled Therapeutics, Inc. Protein microspheres and methods of using them
US6443898B1 (en) * 1989-12-22 2002-09-03 Imarx Pharmaceutical Corp. Therapeutic delivery systems
US5580575A (en) * 1989-12-22 1996-12-03 Imarx Pharmaceutical Corp. Therapeutic drug delivery systems
US5922304A (en) * 1989-12-22 1999-07-13 Imarx Pharmaceutical Corp. Gaseous precursor filled microspheres as magnetic resonance imaging contrast agents
US5501863A (en) * 1990-02-09 1996-03-26 Schering Aktiengesellschaft Contrast media synthesized from polyaldehydes
US5102983A (en) * 1990-04-02 1992-04-07 United States Surgical Corporation Process for preparing foamed, bioabsorbable polymer particles
US5190766A (en) * 1990-04-16 1993-03-02 Ken Ishihara Method of controlling drug release by resonant sound wave
US5711933A (en) * 1990-05-18 1998-01-27 Bracco International B.V. Method of making polymeric gas or air filled microballoons for ultrasonic echography
US5948387A (en) * 1990-06-01 1999-09-07 Imarx Pharmaceutical Corp. Contrast media for ultrasonic imaging
US5310540A (en) * 1990-10-05 1994-05-10 Sintetica Sa Method for the preparation of stable suspensions of hollow gas-filled microspheres suitable for ultrasonic echography
US5518709A (en) * 1991-04-10 1996-05-21 Andaris Limited Preparation of diagnostic agents
US5741522A (en) * 1991-07-05 1998-04-21 University Of Rochester Ultrasmall, non-aggregated porous particles of uniform size for entrapping gas bubbles within and methods
US5456917A (en) * 1993-04-12 1995-10-10 Cambridge Scientific, Inc. Method for making a bioerodible material for the sustained release of a medicament and the material made from the method
US5565215A (en) * 1993-07-23 1996-10-15 Massachusettes Institute Of Technology Biodegradable injectable particles for imaging
US5919434A (en) * 1993-09-03 1999-07-06 Nycomed Imaging As Polymeric surfactant-encapsulated microbubbles and their use in ultrasound imaging
US5870275A (en) * 1993-12-03 1999-02-09 Sanyo Chemical Industries, Ltd. Electrolyte and electronic component using same
US5569468A (en) * 1994-02-17 1996-10-29 Modi; Pankaj Vaccine delivery system for immunization, using biodegradable polymer microspheres
US5620883A (en) * 1994-04-01 1997-04-15 The Johns Hopkins University Living cells microencapsulated in a polymeric membrane having two layers
US5562893A (en) * 1994-08-02 1996-10-08 Molecular Biosystems, Inc. Gas-filled microspheres with fluorine-containing shells
US6333021B1 (en) * 1994-11-22 2001-12-25 Bracco Research S.A. Microcapsules, method of making and their use
US5558082A (en) * 1995-01-09 1996-09-24 Spencer; Robert F. Method of intubating a patient and introducer for use with such method
US5886520A (en) * 1995-01-24 1999-03-23 Canon Kabushiki Kaisha Position sensor having magnetic resistance effect devices for detecting a position of an object
US5611344A (en) * 1996-03-05 1997-03-18 Acusphere, Inc. Microencapsulated fluorinated gases for use as imaging agents
US5837221A (en) * 1996-07-29 1998-11-17 Acusphere, Inc. Polymer-lipid microencapsulated gases for use as imaging agents
US6143276A (en) * 1997-03-21 2000-11-07 Imarx Pharmaceutical Corp. Methods for delivering bioactive agents to regions of elevated temperatures
US6193951B1 (en) * 1997-04-30 2001-02-27 Point Biomedical Corporation Microparticles useful as ultrasonic contrast agents
US6045777A (en) * 1997-06-30 2000-04-04 Acusphere, Inc. Method for enhancing the echogenicity and decreasing the attenuation of microencapsulated gases
US6254852B1 (en) * 1999-07-16 2001-07-03 Dupont Pharmaceuticals Company Porous inorganic targeted ultrasound contrast agents
US20030215394A1 (en) * 2002-05-17 2003-11-20 Short Robert E. Microparticles having a matrix interior useful for ultrasound triggered delivery of drugs into the bloodstream
US6919068B2 (en) * 2002-05-17 2005-07-19 Point Biomedical Corporation Method of preparing gas-filled polymer matrix microparticles useful for echographic imaging
US20060013771A1 (en) * 2002-05-17 2006-01-19 Point Biomedical Corporation Method of preparing gas-filled polymer matrix microparticles useful for echographic imaging
US20050043585A1 (en) * 2003-01-03 2005-02-24 Arindam Datta Reticulated elastomeric matrices, their manufacture and use in implantable devices
US20050043816A1 (en) * 2003-05-15 2005-02-24 Arindam Datta Reticulated elastomeric matrices, their manufacture and use in implantable devices

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060141050A1 (en) * 2002-03-26 2006-06-29 Lerner Itzhak E Drug microparticles
US20080213355A1 (en) * 2005-07-22 2008-09-04 Koninklijke Philips Electronics, N.V. Method and System for in Vivo Drug Delivery
JP2009502772A (ja) * 2005-07-22 2009-01-29 コーニンクレッカ フィリップス エレクトロニクス エヌ ヴィ 生体内の薬物の送達用の方法及びシステム
WO2009075583A1 (en) * 2007-12-10 2009-06-18 Epitarget As Use of particles comprising an alcohol
US20120183949A1 (en) * 2011-01-19 2012-07-19 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Method, device, or system using lung sensor for detecting a physiological condition in a vertebrate subject
US8466206B1 (en) * 2011-12-22 2013-06-18 Eastman Kodak Company Process for preparing porous polymer particles

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